Skeletal mass and load-bearing capacity diminish with aging and the associated hormonal and metabolic changes, contributing to skeletal fractures at corticocancellous sites. Biophysical stimuli may be an effective therapy to counter age-related changes in bone mass, structure and strength. Dynamic mechanical loading is known to regulate skeletal mass and structure. However, little is known about the mechanisms of cancellous bone adaptation to mechanical stimuli, as our the majority of our knowledge of loading and bone formation is based on cortical adaptation. Our overall goal is to test the hypothesis that in vivo cyclic mechanical loading applied to cancellous bone counteracts the osteopenia induced by estrogen withdrawal and aging. To test this hypothesis we have developed a loading device to administer well-controlled physiological compression to the mouse tibia in vivo. Increased cancellous bone mass is produced in the tibial metaphysis of healthy mice with this physiological loading. We now propose to examine the interaction of mechanical loading with estrogen-deficiency and aging. In Aim 1, we will apply controlled mechanical loads to the tibiae of 10-week old mice following ovariectomy. Our loading protocol will be identical to that used for our preliminary studies. For Aim 2, we will apply controlled mechanical loads to 6-month old mice and demonstrate that osteogenic mechanical stimuli will induce bone formation in adult mice in the presence of estrogen. These older mice will already be osteopenic and, therefore, also demonstrate that tissue substrate surface is not the limiting factor in responding to mechanical loading. Finally, in Aim 3, we will examine whether estrogen-deficiency reduces the sensitivity of 6-month old mice to osteogenic loading. For each aim, long-term experiments will demonstrate the steady-state adaptive response and short-term experiments will focus on the cellular mechanisms. Cancellous architecture, material properties, cellular activity and load bearing capacity will be assessed in the tibial metaphysis. Combined, these experiments will demonstrate the efficacy of dynamic mechanical loads for maintaining and enhancing cancellous bone mass and the role of estrogen in this process. These experiments will provide insights into the mechanisms whereby cancellous bone adapts to mechanical loading and into strategies for inhibiting age-related and postmenopausal bone loss.